Most, although not all, studies have demonstrated blunted agonist-stimulated, endothelium-dependent vasorelaxation in the peripheral circulation of patients with essential hypertension. This suggests blunted release of endothelium-dependent relaxation factor (EDRF) or enhanced generation of endothelium-dependent contraction factor (EDCF). In the isolated aorta, there are impaired endothelium-dependent relaxation responses in spontaneously hypertensive rats (SHR) compared to their genetically normotensive controls. This has been attributed to an EDCF, which can inactivate nitrogen oxide (NO). The precise identity of EDCF remains unclear, but its generation and action depend on cyclooxygenase and thromboxane (Tx) A.sub.2 /prostaglandin (PG) H.sub.2 receptors and its actions can be prevented by blockade of oxygen free-radicals (O.sub.2.sup.-). O.sub.2.sup.- and NO interact to produce peroxynitrite, which effectively inactivates physiologic concentrations of NO.
However, in contrast to the aorta, coronary artery endothelium-dependent vasodilation is normal in the SHR heart and there is enhanced release of NO from the perfused SHR heart and enhanced activity of constitutive endothelial cell type (ec) nitric oxide synthase (NOS) in cardiac endothelium of SHR. Thus, organs differ in their regulation of NO generation in genetic hypertension.
Studies in isolated kidneys have shown an enhanced calcium-dependent, constitutive NOS activity in the renal medulla of the SHR and a normal or enhanced endothelium-dependent vasodilator response to bradykinin (Bk) or acetylcholine (Ach). These effects are mediated via NO and endothelium-dependent hyperpolarization factor (EDHF). There is also a normal or enhanced rate of excretion of the NO metabolites nitrite (NO.sub.2) and nitrate (NO.sub.3) from isolated kidneys of SHR and an enhanced basal vasodilator tone mediated by NO in the hydronephrotic kidney of the SHR. The perfused kidney from the SHR also generates an EDCF whose effects oppose the vasorelaxant effects of locally generated EDRF-NO. Afferent arterioles isolated from SHR and perfused in vitro have an enhanced vasoconstrictor response to blockade of NOS with L-NMA. However, in contrast to these results in isolated kidneys or vessels that generally suggest a well-maintained or enhanced NO generation, studies in intact SHR kidneys suggest a diminished role for NO in tubular and vascular regulation. Thus, SHR have impaired pressure natriuresis that may depend on diminished NO since it can be corrected by infusion of L-arginine. They also have enhanced TGF responses that have been ascribed to diminished macula densa-derived NO since there is a blunted response to local microperfusion of nitro-L-arginine (L-NA) into the macula densa. Any defect in NO generation in the juxtaglomerular apparatus (JGA) of the SHR could contribute to heightened TGF responses, enhanced renal vascular resistance (RVR), salt retention, and hypertension.
Recently, it has been shown that microperfusion of nitro-L-arginine (L-NA) into the macula densa enhances TGF responses more in Wistar-Kyoto rats (WKY) than SHR rats.
Dissociation between NOS expression and function in the JGA is seen in Sprague-Dawley rats during changes in salt intake. Dietary salt restriction enhances bNOS mRNA and protein expression in macula densa yet abolishes the enhancement of TGF by local microperfusion of L-NMA into the JGA. In the salt-restricted Sprague-Dawley rat, microperfusion of L-arginine into the JGA blunts TGF and restores a response to microperfusion of L-NMA into the JGA. This effect of L-arginine is presumably due to providing substrate for macula densa NOS since its effects are stereospecific and are prevented by inhibition of NOS with L-NMA.
Tempo, or its 4-hydroxy derivative, Tempol, protects beating cardiomyocytes against oxidative damage in vitro and protects the heart against reperfusion damage in vivo. Retrograde microperfusion of Tempo directly into the macula densa consistently and reversibly blunted TGF responses in both SHR and WKY rat nephrons. This suggests that O.sub.2.sup.- may be formed in the JGA of both hypertensive and control rats and modulate the TGF responses, consistent with the finding of EDCF responses in the renal vessels of SHR and WKY. Despite the high renal blood flow, and the high O.sub.2 tension in renal venous blood, the cells of the renal cortex appear to be quite hypoxic because of a pre-glomerular O.sub.2 shunt resulting in values for PO.sub.2 at surface tubules that cycle around 35 mm Hg. It has been argued that the macula densa cells, being downstream from the highly metabolically active thick ascending limb cells, are normally in a O.sub.2 -compromised environment and that TGF prevents nephron O.sub.2 deficiency.